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中国循证儿科杂志

中国循证儿科杂志 ›› 2018, Vol. 13 ›› Issue (6): 447-451.

• 论著 • 上一篇    下一篇

X连锁中性粒细胞减少症1例报告并文献复习

孟新1,2，侯佳1,2，王莹1，刘俐嫔1，刘璐瑶1，刘丹如1，孙金峤1，王晓川1   

  1. 1 复旦大学附属儿科医院临床免疫科 上海，201102；2 共同第一作者
  • 收稿日期:2018-11-19 修回日期:2018-12-20 出版日期:2018-12-25 发布日期:2018-12-25
  • 通讯作者: 王晓川

A case of X-linked neutropenia and literature review

MENG Xin1,2, HOU Jia1,2, WANG Ying1, LIU Li-pin1, LIU Lu-yao1, LIU Dan-ru1, SUN Jin-qiao1, WANG Xiao-chuan1   

  1. 1 Department of Clinical Immunology, Children's Hospital of Fudan University, Shanghai 201102, China; 2 Co-first author
  • Received:2018-11-19 Revised:2018-12-20 Online:2018-12-25 Published:2018-12-25
  • Contact: WANG Xiao-chuan

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摘要： 目的总结WAS基因功能获得性突变致X连锁中性粒细胞减少症（XLN）的临床及分子特征，提高对该病的认识。方法报告1例先天性中性粒细胞减少症患儿的临床病史资料、常规免疫功能、骨髓细胞形态学特点及二代基因测序结果。对检测到的WAS基因突变行Sanger测序技术验证，采用流式细胞术分析患儿及其父母WAS蛋白表达，采用qPCR分析其WAS基因mRNA水平。分别以“X-linked neutropenia”和“X连锁中性粒细胞减少症”检索主要中英文数据库，检索时间为建库至2018年9月20日，提取文献中主要临床表型和基因型。结果男，6岁5月。自3月龄因发热发现WBC和ANC减少，后6年中WBC和ANC一直低于正常，约每月发热1次,伴反复呼吸道感染，有脓毒血症、EB病毒感染史，无湿疹。血常规示PLT计数和体积正常，WBC数量减少［（2.15±0.5）×109·L-1）］，ANC减少［(0.261±0.086)×109·L-1 ］，NK细胞减少［23.42×106·L-1（1.63%）］。骨髓增生活跃低水平，粒系成熟障碍。二代测序显示WAS基因9号外显子c.881T>C（p.I294T）错义突变，其母为该位点携带者。qPCR显示患儿WAS基因mRNA表达水平降低（为正常人的0.29倍）。流式检测显示患儿WAS蛋白表达量为正常对照的74.5%。PubMed数据库中筛选出XLN病例相关文献23篇，中文数据库0篇，总计18例（2个家系、3例散发），报道4个突变位点（L270P、S272P、I290T、I294T）。加上本文1例（19例）进行临床资料总结，ANC数量减少占84.2%，单核细胞数量减少占72.2%，CD4+/CD8+比值倒置占56.3%，临床上主要表现为反复细菌感染和发热。结论 WAS基因功能获得性突变可导致先天性中性粒细胞减少，临床表现为反复感染，症状不突出，具有WAS mRNA表达减少、WASP蛋白仅轻微降低的分子特征。

Abstract: ObjectiveTo investigate the clinical and molecular characteristics of an X-linked neutropenia patient caused by gain-of-function WAS mutation.MethodsThe patient's clinical data, including infection history, ANC of peripheral blood, bone marrow cell morphology, hematology inherited disease related gene screening, and routine immunology function evaluation were reviewed. Sanger sequencing was done for verification of WAS mutation. The WAS protein and WAS mRNA expression level of the patient and his parents were detected by flow cytometry and qPCR method respectively. The keyword "X-linked neutropenia" was searched for in the main English and Chinese databases by the time of September 20, 2018. The main clinical phenotypes and genotypes were extracted from related articles.ResultsThe 6-year-old boy had persistent severe neutropenia from 3-month old with tendency of bacterial infection and recurrent fever. The quantity and volume of blood platelet were normal, while ANC was severely decreased for about 6 years. Immunoglobulin E was slightly increased, NK cells decreased (1.63%), and CD4+/CD8+ T cells was slightly reversed (0.99). The bone marrow smear showed maturation arrest of neutrophil precursors at the promyelocyte stage. The second-generation sequencing detected a missense mutation in WAS gene exon 9 c.881T>C (p.I294T), and his mother was the carrier. The relative expression of WAS gene was 0.29 times compared to control. WAS protein expressed about 74.5% in this case which was much lower in classic WAS syndrome patients. Two families and 3 sporadic cases, totally 18 cases and 4 mutation sites (L270P, S272P, I290T, I294T) were screened out. Analysis of the 19 cases (including this case) showed that ANC decreased in 84.2% of the cases, monocytes decreased in 72.2%, and the lymphocyte subset analysis showed that CD4+/CD8+ was inverted by 56.3%. Clinically, bacterial infections and fever were found frequently.ConclusionThe gain-of-function mutation of WAS gene can lead to congenital neutropenia which was characterized by recurrent infection without prominent symptoms. Reduced molecular expression of WAS mRNA and slightly reduced WASP protein are main molecular characteristics.